Irish researchers say the young field of gut microbiota is a pharmaceutical and regulatory “dream” with clear targets and pathways.
Gut microbial communities consist of hundreds of abundant bacteria species and perhaps thousands of molecules at physiologically relevant concentrations, a recent paper in Science notes.
“The point of understanding these chemical produced by gut bacteria is we want to harvest them to improve human health,” says Paul O’Toole, gut microbiota researcher at the Alimentary Pharmabiotic Centre in University College Cork, Ireland. One recent success is the drug linaclotide, an E. coli toxin cleverly modified to treat people suffering from constipation due to irritable bowel syndrome.
Discovering the most biologically active molecules produced by the microbiota are critical first steps, yet comparatively little is known about the most abundant small molecules in the gut.
Already researchers are using gut microbiota to identify targets implicated in IDB and irritable bowel syndrome (IBS). O’Toole’s group has looked frailty in the elderly and their gut microbiota, but he points to research also into obesity and type II diabetes.
“We are also quite exciting about cardiovascular disease because some bacterial metabolites have a direct effect on metabolism, which controls the risk for getting thickened arteries [arteriosclerosis],” he explained. To improve health in elderly, dietary interventions are the most likely approach; but for heart disease small molecules are far more likely to be embraced by the pharmaceutical industry.
Patent pending
A researcher at Cleveland Clinic in Ohio has shown how the gut microbiota converts ingredients in diet to a compound called TMA, which is a risk factor for heart disease. “They are talking about filing patents on small molecule inhibitors of the enzymes that convert dietary ingredients into other compounds which are risk factors for heart disease,” says O’Toole.
“We’ve an alternative approach. We are trying to use whole bacteria or bacterial enzymes to get rid of those compounds that promote heart disease, and we have a patent file and a range of papers on the topic.”
Pharma companies have taken a cautious interest in smaller players in this area and therapies for antibiotic-associated diarrhoea have attracted attention. Groups like O’Toole’s have experimented with microbiota transplantation using faecal samples to treat C. difficile infections, as well as for IBD, IBS and diabetes.
‘The dream of the pharmaceutical industry’
“You always worry about giving at-risk patient a collection of bacteria whose properties are essentially unknown. So people are trying to grow single organisms and make artificial stools, something our lab is doing,” said O’Toole.
“These are halfway houses on the way to small molecules, which is the dream of the pharmaceutical industry, because then you have a target, a drug and a well characterised pathway, and that’s what regulatory agencies want too. So we are trying to apply a pharma paradigm to a very immature field,” said the Cork scientist, who estimates that drug filings from microbiome research are at least 5 years away, but will be forthcoming.
“It is such a new field. People are going to conferences scratching their head and saying ‘I never even thought about that possibility’,” he says. The research detailed in the recent review will require a new way of thinking:
“Some of the paradigms [in the review] are based on pathogenicity. But these bugs have coevolved with us for hundreds of thousands of years, carrying out essential functions; instead of trying to kill them, we have to figure out how to exploit them.”